# Coordination of Atr Signaling for Genetic Quality Control, Silencing, and DNA Repair during Meiosis

> **NIH NIH R01** · CORNELL UNIVERSITY · 2024 · $721,137

## Abstract

SUMMARY
Meiosis is the specialized cell division that gives rise to haploid gametes for sexual reproduction. During
prophase I, homologous chromosomes are physically tethered via the formation of the synaptonemal complex
while undergoing DNA double strand break (DSB)-induced recombination. In XY mammals, there is an additional
challenge presented by the sex chromosomes, which synapse only at the Pseudoautosomal Region (PAR),
leaving vast asynapsed regions that trigger a unique chromosome-wide transcriptional silencing mechanism
termed Meiotic Sex Chromosome Inactivation (MSCI). MSCI occurs within the context of the Sex Body (SB), a
membrane-less sub-domain of the nucleus that houses the XY. MSCI is a specialized version of the broader
process of Meiotic Silencing of Unsynapsed Chromatin (MSUC) that occurs in male and female meiosis when
homologs fail to synapse, triggering apoptosis of aberrant germ cells. All of these events are critical to ensure
the formation of viable euploid gametes, underscored by the fact that humans show exceptionally high rates of
meiotic errors leading to miscarriages and birth defects, with non-disjunction of the sex chromosomes, Klinefelter
syndrome, being the most frequent trisomic disorder (1:500 live births). Our labs and others have shown that the
kinase ATR is central to many prophase I events, including DSB repair, synapsis, and MSCI. However, these
numerous overlapping roles have posed a barrier to understanding the precise mechanistic actions of ATR in
meiosis. In the prior funding cycle, we generated novel separation-of-function mouse mutants in ATR regulators
that allow us to dissect specific roles for ATR in MSCI with minimal effects on its other meiotic functions. These
mice bear mutations in TOPBP1, a key ATR activator that also mediates substrate selectivity, and in RAD9A/B,
components of the 911 clamp that helps anchor TOPBP1. Our analysis revealed critical functions of TOPBP1
and 911 in driving ATR functions within the SB, and highlighted essential downstream ATR targets in these
processes such as the RNA:DNA helicase Senataxin (SETX). We hypothesize that the ATR-TOPBP1-911 axis
plays critical roles in establishing the unique chromatin and transcriptional environment required to
initiate, maintain, and terminate MSCI in a temporally restricted manner during meiotic prophase I, and
that this function is dependent on downstream ATR targets including SETX. Utilizing our unique mouse
models in combination with high-resolution genomic tools and cutting-edge proteomic approaches, we will
elucidate the mechanisms by which ATR signaling orchestrates MSCI in male meiosis, and MSUC in male and
female meiosis. Finally, based on our findings that ATR signaling is constantly antagonized, indicative of
prominent roles for phosphatases during MSCI maintenance and termination, we will determine the mechanisms
by which ATR signaling is counteracted by phosphatases to achieve temporally-appropriate shutdown of
transcrip...

## Key facts

- **NIH application ID:** 10905837
- **Project number:** 2R01HD095296-06
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Paula Elaine Cohen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $721,137
- **Award type:** 2
- **Project period:** 2018-09-13 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10905837

## Citation

> US National Institutes of Health, RePORTER application 10905837, Coordination of Atr Signaling for Genetic Quality Control, Silencing, and DNA Repair during Meiosis (2R01HD095296-06). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10905837. Licensed CC0.

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